Whatever the new approaches for therapy of cancers will be in the future, an accurate and specific non-invasive diagnosis on bio-molecular level of tumours and metastases will remain of primary importance. Transformation of normal cells into malignant cells is caused by changes in the genetic material, resulting in subtle but fundamental metabolic changes like increased glucose metabolism and increased amino acid uptake and metabolism. These changes in the metabolic phenotype permit the in-vivo study of tumours using radioactive labelled tracers coupled to SPECT (Single Photon Emission Computed Tomography) or PET (Positron Emission Tomography). PET linked coincidence acquisition allows a better resolution and quantification than SPECT, needed for tumour tracing and dimensioning.
Currently, the use of 18F-FDG (fluoro-deoxyglucose) and PET is the most important technique in nuclear medicine for the study of oncology patients. Although this method is very sensitive, it has two major limitations, namely an avid accumulation in inflammatory lesions and high uptake in the brain, jeopardizing the diagnosis of brain tumours.
It was shown that the use of radioactive amino acids for SPECT and PET could overcome these shortcomings for the larger part. In the late 80's, several 11C-labelled amino acids like methionine and tyrosine, as well as 2-18F-tyrosine (2-18F-Tyr) of high specific activity were used for PET studies. At that time it was believed that a high specific activity was required and that for tumour-specification the labelled amino acid had to be involved in a high rate protein incorporation. None of these amino acids has meanwhile been introduced into routine clinical PET because of the short half life and insufficient in vivo stability of C-11 or complicated radiochemical synthesis resulting in insufficient yield (such as for 2-18F-Tyr).
About the same time, L-3-123I-alpha-methyl-tyrosine (3-123I-IMT) was introduced as a SPECT tracer for brain tumours and is used until now also for other tumours like sarcoma and lymphoma. The uptake of this tracer in tumours occurs for the larger part by the L transport system. The plasma membrane transport system L is in many cells the only (efficient) pathway for the import of large branched and aromatic neutral amino acids. The L-type amino acid transporter 1 (LAT1) is a Na+ independent amino acid transporter and is over-expressed in over-expressed in malignant cell as it plays a critical role in cell growth and proliferation. For functional expression LAT1 requires the heavy chain of the surface antigen 4F2 (heavy chain 4F2hc). The increased accumulation is mainly determined by strongly increased amino acid transport activity rather than incorporation into proteins. A major drawback limiting the applicability of this tracer is however the high renal accumulation.
O-(2-18F-ethyl)-tyrosine (FET) and 18F-alpha-methyl-tyrosine were proposed in 1999 as potential PET tracers. The compounds showed the same uptake properties as IMT. The preparation of these tracers still requires complicated and time consuming synthetic steps and HPLC steps limiting the overall radiochemical yield. They are therefore in practice not very useful.
In the research that led to the invention two new potential SPECT tracers, 2-123I-tyrosine (2-123I-Tyr) and 2-123-I-phenylalanine, were developed. When evaluated in vivo in RIM tumour (rhabdomyo-sarcoma)-bearing rats, these tracers showed high uptake in the tumours (comparable with IMT) while no renal accumulation (10 times less activity in the kidneys than IMT) or high brain uptake was observed. Kinetic studies also revealed that the uptake of radioactive amino acid reflected the amounts of amino acids in the tumour as compared to the blood pool compartment and that no high specific activity is required for the tracer. However, also these tracers are almost limited to SPECT as the positron emitting iodine isotopes 124I and 122I do not have the required radionuclide properties for routine patient PET diagnosis.